The subject of the present invention is the therapeutic use of a human immunodeficiency virus (HIV) protease inhibiting compound as proteasome modulator.
Proteasome, a central enzymatic system in protein degradation both in the cytosol and in the nucleus, is a complex having multiple peptidase activities. One of its functions is the generation of small peptides by intracellular proteolysis, these small peptides being presented to the T lymphocytes so as to initiate immune responses.
It has been shown that peptide aldehydes are proteasome inhibitors and block the degradation of most cellular proteins and the generation of the peptides presented at the surface of antigen presenting cells, in association with the molecules of the major histocompatibility complex class I (Rock et al., Cell, 1994, vol. 78, 761-771). Several patent applications disclose, moreover, proteasome inhibitors which can be used in the treatment of diseases in which a loss of body mass is observed (WO 95/24 914), diseases resulting from cell proliferation (WO 98/13 061) and more generally diseases involving the proteolytic function of the proteasome, such as in particular inflammatory diseases and cancers (WO 96/32 105; WO 96/13 266).
The subject of the present invention is the use of at least one human immunodeficiency virus (HIV) protease inhibiting compound chosen from ritonavir, saquinavir, or one of their pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable vehicle, for the manufacture of a medicament intended for modulating the proteasome.
Surprisingly, the authors of the present invention have discovered that certain human immuno-deficiency virus (HIV) protease inhibiting compounds exhibit a modulatory action on the activity of the proteasome.
They are:
ritonavir, and its pharmaceutically acceptable salts, a proprietary medicinal product containing ritonavir as active ingredient, being Norvir(copyright) (Abbott);
and saquinavir, and its pharmaceutically acceptable salts, a proprietary medicinal product containing saquinavir, in the form of saquinavir mesylate as active ingredient, being Invirase(copyright) (Roche).
Ritonavir, saquinavir or their salts may be used alone or in the form of a mixture. The combination of ritonavir and saquinavir is particularly advantageous because it makes it possible to enhance the pharmacokinetics of saquinavir, whose degradation is slowed down by the presence of ritonavir.
These inhibitors (described in Patent Applications WO 94/14 436 and EP 432 695) of the human immunodeficiency virus (HIV) protease are widely used in the treatment of AIDS. These compounds block viral replication by specifically inhibiting the viral protease which allows cleavage of the viral protein precursors to mature viral proteins. The tritherapy using such a protease inhibitor combined with two nucleoside analogues is thus currently the most effective strategy for the treatment of an HIV infection.
The subject of the present invention is therefore the use of at least one human immuno-deficiency virus (HIV) protease inhibiting compound chosen from ritonavir, saquinavir, or one of their pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable vehicle, for the manufacture of a medicament intended for modulating the proteasome.
The authors of the present invention have thus discovered that ritonavir and saquinavir inhibited the xe2x80x9cchymotrypsin-likexe2x80x9d activity of the proteasome and increased the xe2x80x9ctrypsinxe2x80x9d activity of the proteasome.
The modulation of the proteasome makes it possible to act on a number of events xe2x80x9cdownstreamxe2x80x9d.
The authors of the present invention have more particularly demonstrated that these human immuno-deficiency virus (HIV) protease inhibiting compounds exhibiting a modulatory action on the activity of the proteasome made it possible to modify the presentation of antigens in combination with the major histo-compatibility complex class I (MHC1), at the surface of the cells and consequently inhibited or modified the activation of the CD8+ cytotoxic T lymphocytes. These compounds therefore have the crucial advantage of not directly influencing the activity of the helper T lymphocytes at therapeutic concentrations. Human immunodeficiency virus (HIV) protease inhibiting compounds exhibiting a modulatory action on the activity of the proteasome are therefore particularly useful for the prevention and/or treatment of conditions in which an inadequate response, for example an excessive response, of the CD8+ cytotoxic T lymphocytes is observed. More generally, the conditions aimed at are those for whose treatment a modulation (such as in particular a decrease) in the immune response provided by the CD8+ cytotoxic T lymphocytes is sought.
The HIV protease inhibiting and proteasome modulating compounds according to the invention exhibit, moreover, an apoptosis modulating activity, a consequence of the modulation of the proteasome (Nagata et al., 1997, Cell, 88:355-365: Ruggieri et al., 1997, Virology, 229:68-76: WO 98/13 061).
Among the conditions for which it is advantageous to modulate the activity of the proteasome, there may be mentioned in particular inflammatory diseases, infectious diseases and/or those for whose treatment modulation or control of apoptosis is desired. Those more particularly aimed at are:
autoimmune diseases, such as type 1 diabetes, multiple sclerosis, psoriasis, contact hypersensitivity or rheumatoid arthritis;
viral conditions, in particular infections with noncytopathogenic viruses such as infections with the hepatitis viruses, in particular the hepatitis B virus and the hepatitis C virus;
transplant rejections, and
diseases resulting from abnormal cell proliferation, such as cancers.
It is understood that acquired immunodeficiency syndrome (AIDS) is not a condition aimed at since the decrease in the number of CD8+ T lymphocytes is not desired in the treatment of this syndrome.
The subject of the present invention is also a method of screening human immunodeficiency virus (HIV) protease inhibiting compounds, consisting in testing the said compounds for their capacity to modulate the activity of the proteasome.
This includes in particular screening known HIV protease inhibitors, such as in particular the inhibitors described in Patent Applications WO 94/14 436 and EP 432 695 for the evaluation of their proteasome activity modulating action. Such a screening test is acceptable to persons skilled in the art. The HIV protease inhibiting compounds may in particular be tested on isolated proteasomes by determining the capacity of these compounds to modulate the peptidase activity of the proteasome (Cerundolo V et al., Eur. J. Immunol., 27, 336-341 (1997); Groettrup M. et al., J. Biol. Chem. 270, 23808-23815 (1995)). It is also possible to carry out functional tests which determine the capacity of these compounds to modulate the presentation of the antigens to T lymphocyte clones (Gervois N. et al., J. Exp. Med., 183, 2403-2407 (1996); York et al., Annu. Rev. Immunol., 14, 369-396 (1996); Rock K. L. et al., Proc. Natl. Acad. Sci. USA 94, 10850-10855 (1997)).
The medicament prepared in accordance with the present invention and containing at least one proteasome activity modulating compound, in combination with a pharmaceutically acceptable vehicle, may be in the form of a pharmaceutical composition intended for administration by the oral route, for example in the form of a tablet, a gelatin capsule, an oral solution and the like, or by the rectal route, for example in the form of a suppository. It may also be administered by the parenteral route, in particular in the form of an injectable solution, in particular by the intravenous, intradermal or subcutaneous route, and the like. It may finally be in the form of a pharmaceutical composition intended for topical administration, such as an ointment. Such a formulation is particularly advantageous in the case of the treatment of psoriasis and of contact hypersensitivities.
The medicament prepared in accordance with the present invention preferably contains from 1 to 2000 mg, preferably from 100 to 500 mg, of the said compound exhibiting a proteasome activity modulating action.
The present invention also relates to a method of therapeutic treatment in which a therapeutically effective quantity of at least one HIV protease inhibiting compound chosen from ritonavir, saquinavir or one of their pharmaceutically acceptable salts, alone or in the form of a mixture, in combination with a pharmaceutically acceptable vehicle, is administered to a patient suffering from a condition for whose treatment modulation of the proteasome is desired.
The dosage depends on the seriousness of the condition, the age and weight of the patient. It may be in particular from 100 to 1500 mg per day, preferably from 600 to 1200 mg per day.
The figures and the examples below illustrate the invention without limiting it.